Grx5 glutaredoxin plays a central role in protection against protein oxidative damage in Saccharomyces cerevisiae

Glutaredoxins are members of a superfamily of thiol disulfide oxidoreductas es involved in maintaining the redox state of target proteins. In Saccharom yces cerevisiae, two glutaredoxins (Grx1 and Grx2) containing a cysteine pa ir at the active site had been characterized as protecting yeast cells agai nst oxidative damage. In this work, another subfamily of yeast glutaredoxin s (Grx3, Grx4, and Grx5) that differs from the first in containing a single cysteine residue at the putative active site is described. This trait is a lso characteristic for a number of glutaredoxins from bacteria to humans, w ith which the Grx3/4/5 group has extensive homology over two regions. Mutan ts lacking Grx5 are partially deficient in growth in rich and minimal media and also highly sensitive to oxidative damage caused by menadione and hydr ogen peroxide. A significant increase in total protein carbonyl content is constitutively observed in grx5 cells, and a number of specific proteins, i ncluding transketolase, appear to be highly oxidized in this mutant. The sy nthetic lethality of the grx5 and grx2 mutations on one hand and of grx5 wi th the grx3 grx4 combination on the other points to a complex functional re lationship among yeast glutaredoxins, with Grx5 playing a specially importa nt role in protection against oxidative stress both during ordinary growth conditions and after externally induced damage. Grx5-deficient mutants are also sensitive to osmotic stress, which indicates a relationship between th e two types of stress in yeast cells.